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The BioPSI Project: Representation and Simulation of Molecular Processes

The BioPSI Project: Representation and Simulation of Molecular Processes. Aviv Regev Bill Silverman Udi Shapiro. Pathway Informatics: From molecule to process. Genome, transcriptosome, proteome. Regulation of expression; Signal Transduction; Metabolism. Information about Dynamics

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The BioPSI Project: Representation and Simulation of Molecular Processes

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  1. The BioPSI Project: Representation and Simulation ofMolecular Processes Aviv RegevBill SilvermanUdi Shapiro

  2. Pathway Informatics: From molecule to process Genome, transcriptosome, proteome Regulation of expression; Signal Transduction; Metabolism

  3. Information about Dynamics Molecular structure Biochemical detail of interaction The Power to simulate analyze compare Formal semantics Our Goal: A formal representation language for molecular processes

  4. Biochemical networks asconcurrent computation • Concurrent, compositional • Mobile (dynamic wiring) • Modular, hierarchical

  5. The p-calculus (Milner, Walker and Parrow 1989) • A program specifies a network of interacting processes • Processes are defined by their potential communication activities • Communication occurs on complementary channels, identified by names • Communication content: Change of channel names (mobility) • Stochastic version (Priami 1995) : Channels are assigned rates

  6. ERK1 SYSTEM ::= … | ERK1 | ERK1 | … | MEK1 | MEK1 | …ERK1 ::= (new internal_channels) (Nt_LOBE |CATALYTIC_CORE|Ct_LOBE) Domains, molecules, systems ~ Processes Processes P – ProcessP|Q – Two parallel processes

  7. MEK1 ERK1 T_LOOP (tyr)::= tyr? [tyr].T_LOOP(tyr) Y KINASE_ACTIVE_SITE::= tyr! [p-tyr] . KINASE_ACTIVE_SITE Complementary molecular structures ~Global channel names and co-names Global communication channels x ? [y] –Input into y on channel xx ! [z] – Output z on channel x

  8. Ready to send p-tyron tyr! Ready to receive on tyr? MEK1 ERK1 tyr! [p-tyr] . KINASE_ACTIVE_SITE + … | … + tyr? [tyr]. T_LOOP Y Actions consumed alternatives discarded KINASE_ACTIVE_SITE| T_LOOP {p-tyr/ tyr} pY Communication and global mobility p-tyr replaces tyr Molecular interaction and modification ~Communication and change of channel names

  9. ERK1 ERK1 ::= (newbackbone)(Nt_LOBE |CATALYTIC_CORE |Ct_LOBE) Compartments (molecule,complex,subcellular)~ Local channels as unique identifiers Local restricted channels (new x) P – Local channel x, in process P

  10. MP1 (new backbone) mp1 ! [backbone] . backbone ! [ … ] | mp1 ? [cross_backbone] . cross_backbone ? […] MEK1 ERK1 Complex formation ~ Exporting local channels Communication and scope extrusion (new x) (y ! [x]) – Extrusion of local channel x

  11. The Simulation Engine Flat Concurrent Prolog • Ability to pass logical variables in messages ( mobility) • Guarded atomic unification ( synchronized communication) • Previous implementations lack in synchronicity and choice (Stochastic) Pi-calculus Flat Concurrent Prolog C

  12. Brate* Type* *Stochastic version(Priami, Regev et al. 2000) The Simulation Engine Channel • Processes (FCP procedures) send requests to channels (FCP objects) • The channel synchronizes the completion of send and receive requests and withdrawal of alternative choices • Debugging and tracing tools Name Send list Receive list

  13. GF GF RTK RTK SHC GRB2 SOS MKP1 RAS PP2A GAP MKK1 RAF ERK1 IEP MP1 IEP J F IEG The RTK-MAPK pathway • 16 molecular species • 24 domains; 15 sub-domains • Four cellular compartments • Binding, dimerization, phosphorylation, de-phosphorylation, conformational changes, translocation • ~100 literature articles • 250 lines of code

  14. Mutation Analysis Most were buffered by the system except at extreme “doses” Quantitative Functional

  15. Levchenko et al., 2000 Why Pi ? • Compositional • Molecular • Incremental • Preservation through transitions • Straightforward manipulation • Modular • Scalable • Comparative

  16. The BioPSI team Udi Shapiro (WIS) Bill Silverman (WIS) Aviv Regev (TAU, WIS) BioPSI Collaborations Naama Barkai (WIS) Corrado Priami (U. Verona) www.wisdom.weizmann.ac.il/~aviv

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